The Alzheimer's Disease Research Center (ADRC) at the Johns Hopkins Medical Institutions (JHMI) has a commitment to investigations of aging and age-associated diseases, particularly Alzheimer's disease (AD). Because of the importance of age and genetic factors in the etiologies of AD, the principal research focus of our ADRC is on the roles of age and genes in these processes. Thus, with the support of Cores, the research in Kawas' Project focuses on behavior-brain correlations in intact aged individuals, elderly subjects with mild cognitive impairments, and cases of AD at various stages of the disease. Of particular importance are the studies of the Baltimore Longitudinal Study of Aging (BLSA) cohort, a unique, extraordinarily well-characterized group of subjects that have been followed for up to 30 years. Some of these individuals will have serial imaging studies. Moreover, these elderly subjects, who have detailed neuropsychological examinations, have consented to autopsy so that brain tissues will be available for research. Supported by the Neuropathology Core, Projects 18-20 take advantage of transgenic technologies: to produce mice with mutations in the amyloid precursor protein (APP) gene linked to familial AD or hereditary cerebral hemorrhage with amyloid, Dutch type; to introduce SOD1 genes with mutations linked to familial amyotrophic lateral sclerosis into the mouse germline; and to overexpress or ablate the APP gene. These animals will be studied using a variety of neurobiological strategies that have proved to be very successful in other animal models of age-associated disorders. These models will be of great value in testing the etiological roles of these mutations in disease, in examining the character/evolution of the pathology, in determining mechanisms of cell dysfunction/death, and eventually, in testing novel therapies. Additional studies relevant to aging and neurodegenerative diseases are supported by our Pilots. Finally, our ADRC is committed to training young physicians and scientists and in disseminating information concerning age-associated diseases to families, caregivers, and other health professionals.